Targeted gene delivery involves broadening viral tropism to infect previously nonpermissive cells, replacing viral tropism to infect a target cell exclusively, or stealthing the vector against nonspecific interactions with host cells and proteins. These approaches offer the potential advantages of enhanced therapeutic effects, reduced side effects, lowered dosages, and enhanced therapeutic economics. This review will discuss a variety of targeting strategies, both genetic and nongenetic, for re-engineering the tropism of two representative enveloped and nonenveloped viruses, murine retrovirus and adeno-associated virus. Basic advances in understanding the structural biology and virology of the parent viruses have aided rational design efforts to engineer novel properties into the viral attachment proteins. Furthermore, even in the absence of basic, mechanistic knowledge of viral function, high-throughput library and directed evolution approaches can yield significant improvements in vector function. These two complementary strategies offer the potential to gain enhanced molecular control over vector properties and overcome challenges in generating high titer, stealthy, retargeted vectors.